Ambrisentan and its analogue and their pharmaceutically acceptable salts were disclosed in U.S. Pat. No. 5,932,730. The disclosed process comprises of reacting benzophenone with methyl chloroacetate in presence of sodium methoxide in tetrahydrofuran providing 3,3-diphenyl oxirane-2-carboxylic acid methyl ester, which on in-situ treatment with methanol and BF3/Et2O in diethyl ether provides 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester. Thus obtained methyl ester is hydrolyzed and then resolved with L-proline methyl ester to provide (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. The conversion of this intermediate into ambrisentan is not disclosed.
The drugs of future 2005, 30(8), 765-770 disclosed the preparation of racemic ambrisentan. The racemic ambrisentan obtained is converted into active compound by resolving with chiral amine. But the experimental details were not disclosed for the same.
An article published in ‘Research Disclosure’ disclosed a process which comprises of the condensation of (S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid and 4,6-dimethyl-2-(methylsulfonyl)pyrimidine using lithium amide in dimethyl formamide, followed by extraction of the reaction mixture with tertiary butyl ether. The ether layer is concentrated and ambrisentan was isolated by the addition petroleum ether. The usage of ether solvents is commercially not recommendable.
Organic Process Research & Development 2001, 5, 16-22 and J. Med. Chem, 1999, 41, 3026-3032 disclosed a process for the preparation of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester, a key intermediate by esterification of its acid to provide the ester as a crude oil. Repeated the same reactions using high pure (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid only provided ester of maximum 60% purity. Hence when the ester intermediate was used for the preparation of Endothelin receptor antagonists, it provided the products with low yield and high levels of impurity.
Hence the focus of the invention was to prepare (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester of high purity, so that it could be used to prepare Endothelin receptor antagonists with substantially high yields and also in a quality which could meet the specifications set by of ICH.
(S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester has been reported as an oil. In the present invention it was isolated as a crystalline solid which not only improved the yields but also its quality. This when used in the subsequent stages provided the Endothelin receptor antagonists compound in high yields and of high purity.
The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. There is a need in the art for the preparation of new polymorphic form of Endothelin receptor antagonists, its intermediates and their salts.
The aim of the present invention is to overcome the drawbacks of prior art and to provide an improved process for the preparation of high pure Endothelin Receptor Antagonists and their intermediates such as (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester, its salts as well as their crystalline forms.